Abstract The Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Trial is a funded, double-blind, placebo-controlled, multicenter, randomized clinical trial testing the hypothesis that peri-op fish oil will reduce occurrence of post-op atrial fibrillation or flutter (AF) in 1516 patients undergoing cardiac surgery (CS). In this Ancillary Study, we will add the evaluation of a second major CS complication to the study, that of post-op cognitive decline, and assess key circulating and tissue biomarkers to investigate key novel mechanistic pathways whereby post-op cognitive decline and AF may each occur and also test the hypothesis that fish oil decreases post-op AF and possibly cognitive decline by preventing oxidative stress and subsequent inflammation. As a nested Ancillary Study, this provides a highly cost- and time- efficient opportunity to perform innovative investigations on highly relevant biologic pathways as well as potential novel treatments for post-op AF and cognitive decline, the two most common complications of CS. These findings will provide the most comprehensive evaluation to-date of how oxidative and inflammatory pathways mediate pathogenesis of post-op cognitive decline and AF, and directly test whether a low cost, low risk dietary supplement affects local and systematic responses to CS or alters risk of post-op cognitive injury. The results will lead to an explosion of future innovative research aims and hypotheses linked to these scientific issues as well as novel targets for new drugs or other technologies to minimize the insults from CS. At the same time, our ability to directly determine in a large controlled trial the effects of peri-op fish oil on CS-related oxidative stress, inflammation, and cognitive decline will stimulate exciting future research but also, if successful, directly improve practice of health care delivery. PUBLIC HEALTH RELEVANCE: Project Narrative Although post-operative atrial fibrillation and cognitive decline are extremely common adverse outcomes following cardiac surgery, neither the pathophysiology of nor potentially effective treatments for these complications are well-understood This project will be the first of its kind to address these two most common complications of cardiac surgery through a unified approach that could yield long-term growth and advances in a new genre of interdisciplinary inquiry, with tremendous implications for both future research and clinical patient care. (End of Abstract)